Human immunodeficiency virus (HIV), the etiological agent of acquired immunodeficiency syndrome (AIDS), enters cells by binding its envelope glycoprotein (Env) to receptor molecules and fusing its membrane with the cell membrane. Understanding how the HIV envelope glycoprotein interacts with receptor molecules and antibodies is critical for elucidating the mechanisms of HIV infection, and design of new antiretroviral treatments and vaccines. Our major goal is the elucidation of the mechanisms of the initial stages of HIV entry into cells, and the development of novel vaccine immunogens and inhibitors based on human monoclonal antibodies. We identified two novel human broadly HIV neutralizing antibodies, Fab X5 and m14, by using an antigen and a methodology we developed. We further improved the potency of these antibodies (m6, m9 and IgG1 m14) and they are now among the very few most potent and broadly neutralizing antibodies against HIV available today. We are currently developing even more potent and broadly neutralizing fusion proteins based on these antibodies that we hope will go to clinical trials. We found that these antibodies bind to highly conserved viral structures, and currently are also attempting to identify small molecule inhibitors of HIV entry that target these structures by screening of libraries of small molecules. NCI filed three patent applications for these antibodies, and currently several companies including Tanox, Medimune and Virosys, are in various stages of negotiaion, licensing and CRADAs, for their development as therapeutics. These antibodies were requested by more than 30 research groups from USA and Europe and, are currently extensively investigated. We are further developing an HIV vaccine immunogen based on the tethered envelope glycoproteins (Envs) we recently developed based on our new concept that the use of flexible linkers to join gp120 and gp41 will lead to exposure of conserved epitopes. We have extensively characterized the epitopes of the new broadly HIV neutralizing antibodies we identified, including the solution of the crystal structure of X5 and its docking to the known gp120 core crystal structure. Based on this information we designed new vaccine immunogens that may have the potential to elicit in vivo those antibodies - an approach known as retrovaccinology - a termed coined by our collaborator Dennis Burton. We have been also developing vaccine immunogens based on Env-receptor complexes. Currently a major challenge for the HIV vaccine research is to elicit potent broadly neutralizing antibodies. There are several known such antibodies and experiments by other groups have shown that these antibodies can prevent infection in monkeys; however, the efforts to design immunogens that could elicit these antibodies in vivo have not been successful yet. We hope that the new immunogens, we are developing based on detailed information of the epitopes of the antibodies we discovered, will help to solve this fundamental problem and perhaps result in sterilizing immunity which is an ultimate goal in vaccine development.